Mechanisms of action and clinical efficacy of NMDA receptor modulators in mood disorders
Mehdi Ghasemi 1, Cristy Phillips 2, Atoossa Fahimi 3, Margaret Windy McNerney 3, Ahmad Salehi 4
Neurosci Biobehav Rev. 2017 Sep:80:555-572. doi: 10.1016/j.neubiorev.2017.07.002. Epub 2017 Jul 13.
Abstract
Although the biogenic amine models have provided meaningful links between clinical phenomena and pharmacological management of mood disorders (MDs), the onset of action of current treatments is slow and a proportion of individuals fail to adequately respond. A growing number of investigations have focused on the glutamatergic system as a viable target. Herein we review the putative role of N-methyl-d-aspartate (NMDA) signaling in the pathophysiology of MDs. Prompting this focus are several lines of evidence: 1) altered glutamate and NMDA receptor (NMDAR) expression and functioning; 2) antidepressant effects of NMDAR signaling blockers; 3) interaction between conventional therapeutic regimens and NMDAR signaling modulators; 4) biochemical evidence of interaction between monoaminergic system and NMDAR signaling; 5) interaction between neurotrophic factors and NMDAR signaling in mood regulation; 6) cross-talk between NMDAR signaling and inflammatory processes; and 7) antidepressant effects of a number of NMDA modulators in recent clinical trials. Altogether, these studies establish a warrant for the refinement of novel compounds that target glutamatergic mechanisms for the treatment of MDs.
Keywords: BDNF; Bipolar disorder; Glutamate; Inflammation; Ketamine; Major depressive disorder; Mood disorders; NMDA receptor; NMDA receptor antagonists; Norepinephrine; Serotonin.
https://pubmed.ncbi.nlm.nih.gov/28711661/
生体アミンモデルは、臨床現象と気分障害（MD）の薬理学的管理との間に意味のあるつながりを提供しているが、現在の治療法の作用発現は遅く、一部の患者は適切に反応しない。実行可能なターゲットとしてグルタミン酸系に着目した調査が増えている。ここでは、MDの病態生理学におけるN-メチル-d-アスパラギン酸（NMDA）シグナル伝達の推定役割についてレビューする。これに焦点を当てるきっかけとなったのは、1）グルタミン酸およびNMDA受容体（NMDAR）の発現および機能の変化、2）NMDARシグナル伝達阻害剤の抗うつ効果、3）従来の治療レジメンとNMDARシグナル伝達調節因子との相互作用、4）モノアミン系とNMDARシグナル伝達との相互作用の生化学的証拠、5）気分調節における神経栄養因子とNMDARシグナル伝達との相互作用、6）NMDARシグナル伝達と炎症プロセスとのクロストーク、などのいくつかの証拠である。 7) 最近の臨床試験で、いくつかの NMDA 調節剤の抗うつ効果が明らかになった。これらの研究は、MD の治療にグルタミン酸作動性メカニズムを標的とする新規化合物の改良の必要性を裏付けるものである。
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